Molecular Dynamics Simulation of Human Pancreatic Lipase and Lipase-colipase Complex: Insight into the Structural Fluctuations and Conformational Changes
International Journal of Computational and Theoretical Chemistry
Volume 8, Issue 1, June 2020, Pages: 19-26
Received: Jan. 25, 2020;
Accepted: Feb. 17, 2020;
Published: Feb. 28, 2020
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Sikiru Akinyeye Ahmed, Department of Chemistry, Kwara State University, Malete, Ilorin, Nigeria
Nizakat Ali, International Centre for Chemical and Biological Sciences (ICCBS), University of Karachi, Karachi, Pakistan
Urooj Qureshi, International Centre for Chemical and Biological Sciences (ICCBS), University of Karachi, Karachi, Pakistan
Ruqaiya Khalil, International Centre for Chemical and Biological Sciences (ICCBS), University of Karachi, Karachi, Pakistan
Zaheer-Ul Haq Qasmi, International Centre for Chemical and Biological Sciences (ICCBS), University of Karachi, Karachi, Pakistan
Although the structure of Human Pancreatic Lipase has been documented through the X-ray crystallography, the knowledge about the molecular rearrangement and dynamic equilibrium in the structure (particularly in the catalytic triad and lid domains) is very scanty. The structural fluctuations and conformational changes undergo by Human Pancreatic Lipase (HPL) with and without colipase were computationally investigated through molecular dynamics simulation technique using GROMACS 2018.4, MOE 2016.0801 and VMD softwares in order to gain insight into the complex transitions at different domains. The structural stability was revealed vis-a-vis Root Mean Square Deviation (RMSD) and Root Mean Square Fluctuations (RMSF) plots. The levels of compactness/folding and conformational changes of the protein were determined using Radius of gyration and secondary analysis respectively. Salt bridge analysis gives more ionic pairs interactions than experimentally determined results. Results show that though both proteins are stable, lipase-colipase complex is more deviated and flexible than lipase. Also, additional information regarding the conformational transitions, interactions and dynamics that govern stability of lipase-colipase complex which were ‘hidden’ to experimental techniques were revealed.
Sikiru Akinyeye Ahmed,
Zaheer-Ul Haq Qasmi,
Molecular Dynamics Simulation of Human Pancreatic Lipase and Lipase-colipase Complex: Insight into the Structural Fluctuations and Conformational Changes, International Journal of Computational and Theoretical Chemistry.
Vol. 8, No. 1,
2020, pp. 19-26.
Veeramachaneni G. K, Raj K. K, Chalasani L. M, Bondili J. S, Talluri V. R. (2015): High-throughput virtual screening with e-pharmacophore and molecular simulations study in the designing of pancreatic lipase inhibitors. Drug Design, Development and Therapy. 2015: 9 4397-4412.
Canaan, S., Roussel, L., Verger, R. and Cambillau, C. (1999). Gastric lipase: crystal structure and activity. Biochimica et Biophysica Acta -Molecular and Cell Biology of Lipids, 1441: 197-204.
Lowe, M. E. (1997). Structure and function of pancreatic lipase and colipase. Annual Review of Nutrition, 17: 141-158.
Winkler, F. K., Darcy, A. and Hunziker, W. (1990). Structure of Human Pancreatic Lipase. Nature, 343; 771-774.
van Tilbeurgh, H., Egloff, M. P., Martinez, C., Rugani, N., Verger, R., and Cambillau, C. (1992) Interfacial activation of the lipase-procolipase complex by mixed micelles revealed by X-ray crystallography Nature, 362, 814-420.
van Tilbeurgh, H, Roussel, A., Lalouelln J., and Cambillau, C. (1994); Lipoprotein Lipase: Molecular model based on the Pancreatic Lipase X-Ray structure: Consequences for Heparin binding and catalysis, Journal of Biological Chemistry, 269 (6), 4626-4633.
Freie A. B., Ferrato, F., Carrière, F., and Lowe, M. E (2006): Val407 and Ile408 in the β5’ Loop of Pancreatic Lipase Mediate Lipase-Colipase Interactions in the Presence of Bile Salt Micelles. Journal of Biological Chemistry, 281 (12), 7793–7800.
Bauer, E., Jakob, S. and Mosenthin, R. (2005). Principles of physiology of lipid digestion. Asian -Australasian Journal of Animal Sciences, 18; 282-295.
Miled, N., Canaan, S., Dupuis, L., Roussel, A., Riviere, M., Carriere, F., de Caro, A., Cambillau, C. and Verger, R. (2000). Digestive lipases: from three-dimensional structure to physiology. Biochimie, 82: 973-986.
Cygler, M. and Schrag, J. D. (1997). Structure as basis for understanding interfacial properties of lipases. Methods in Enzymology, 284: 3-27.
Egloff, M. P., Marguet, F., Buono, G., Verger, R., Cambillau, C. and van Tilbeurgh, H. (1995). The 2.46Ao Resolution structure of the pancreatic lipase-colipase complex inhibited by a C11 alkyl phosphonate. Biochemistry 34, 2751-2762.
Egloff, M. P., Sarda, L., Verger, R., Cambillau, C., & Tilbeurgh, H. V. (1995). Crystallographic study of the structure of colipase and of the interaction with Pancreatic lipase. Protein Science, 4 (1), 44-57.
Bourne Y, Martinez C, Kerfelec B, Lombardo D, Chapus C, Cambillau C. (1994). Horse pancreatic lipase. The crystal structure refined at 2.3Ao resolution. Journal of Molecular Biology, 238 (5): 709–732.
Wilde, P. J. and Chu, B. S. (2011). Interfacial and colloidal aspects of lipid digestion. Advances in Colloid and Interface Science, 165: 14-22.
Brockman, H. (2002). Colipase-induced reorganization of interfaces as a regulator of lipolysis. Colloids and Surfaces B: Biointerfaces, 26: 102-111.
Childers M. C and Daggett V. (2017): Insight from molecular dynamics simulations for computational protein design. Molecular System Design and Engineering. 2, 9-33.
Childers, M. C, and Daggett, V. (2018): Validating Molecular Dynamics Simulations against Experimental Observables in Light of Underlying Conformational Ensembles. Journal of Physical Chemistry. B, 2018, 122 (26), 6673–6689.
Aloulou, A., Frikha, F., Noiriel, A., Ali, M. B., Abousalham, A., (2014): Kinetic and structural characterization of triacylglycerol lipases possessing phospholipase A1 activity. Biochimica et Biophysica Acta, 1841: 581–587.
Barbe, S., Corte´, J., Sime´on, T., Monsan, P., Remaud-Sime´on, M., Andre´, I. (2011). A mixed molecular modeling-robotics approach to investigate lipase large molecular motions. Proteins. 79 (8): 2517-29.
James J. J, Lakshmi B. S, Raviprasad V, Ananth M. J, Kangueane P and Gautam P. (2003): Insights from molecular dynamics simulations into pH-dependent enantioselective hydrolysis of ibuprofen esters by Candida rugosa lipase. Protein Engineering 16: 1017–1024.
Selvan A., Seniya C., Chandrasekaran S. N., Siddharth N., Anishetty S., Pennathur G. (2010): Molecular dynamics simulations of human and dog gastric lipases: Insight into domain movements. FEEBS Letters. 584: 4599-4605.
van Tilbeurgh, H., Sarda, L., Verger, R. and Cambillau, C. (1992). Structure of the pancreatic lipase-procolipase complex. Nature, 359: 159-162.
Berman, H. M., Westbrook, J., Feng, Z., Gilland, G., Bhart, T. N., Weissig, H., Shindyalov, I. N and Bourne, P. E. (2000): The Protein Data Bank. Nucleic Acids Research, 28, 235-242.
Berendsen, H. J. C., van der Spoel, D. and van Drunen, R. (1995): GROMACS: a message-passing parallel molecular dynamics implementation. Computational Physics Communications, 91, 43-56.
Lindahl, E., Hess, B. and van der Spoel, D. (2001): GROMACS 3.0: a package for molecular simulation and trajectory analysis. Journal of Molecular Model, 7, 306-317.
Kutzner, C., Páll, S., Fechner, M., Esztermann, A., Groot, B. L., Grubmüller. H. (2015): Best bang for your buck: GPU nodes for GROMACS biomolecular simulations. Journal of Computational Chemistry, 36, 1990–2008.
Berendsen, H. J. C., Grigera, J. R. and Straatsma, T. P. (1987): The missing term in effective pair potentials. Journal of Physical Chemistry. 91 (24), 6269-6271.
Kaminski, G. A., Friesner, R. A., Tirado-Rives, J. and Jorgensen, W. L. (2001): Evaluation and Reparametrization of the OPLS-AA Force Field for Proteins via Comparison with Accurate Quantum Chemical Calculations on Peptides. Journal of Physical Chemistry B. 105, 6474-6487.
Humphrey, W., Dalke, A. and Schulten, K. (1996) VMD: visual molecular dynamics. Journal of Molecular Graphics, 14, 33-38.
Bezzine, S., Carrière, F., De Caro, J., Verger, R. and De Caro, A (1998): Human Pancreatic Lipase: An Exposed Hydrophobic Loop from the C-terminal Domain May Contribute to Interfacial Binding. Biochemistry 37, 11846-11855.
Galzitskaya, O. V., Garbuzynskiy, S. O. (2006) Entropy capacity determines protein folding. Proteins, 63, 144–154.
Marques, S. M., Bednar, D., and Damborsky, J. (2019): Computational Study of Protein-Ligand Unbinding for Enzyme Engineering. Frontiers in Chemistry. 6: 650.
Ishak, S. N. H., Aris, S. N. A. M., Halim K. B. A., Ali, M. S. M., Leow, T. C., Kamarudin, N. H. A, Masomian, M. and Rahman, R. N. Z. R. A (2017) Molecular Dynamic Simulation of Space and Earth-Grown Crystal Structures of Thermostable T1 Lipase Geobacillus zalihae Revealed a Better Structure. Molecules, 22, 1574.
Jennens, M. L. and Lowe M. E (1994): A surface loop covering the active site of Human Pancreatic Lipase influences interfacial activation and lipid binding. Journal of Biological Chemistry, 209 (41), 25470 -25474.
Withers-Martinez, C., Carrière, F., Verger, R., Bourgeois, D. and Cambillau, C. (1996) A pancreatic lipase with a phospholipase A1 activity: crystal structure of a chimeric pancreatic lipase-related protein 2 from guinea pig. Structure, 4: 1363–1374.
Takano K, Tsuchimori K, Yamagata Y, Yutani K. (2000). Contribution of salt bridges near the surface of a protein to the conformational stability. Biochemistry. 39 (40): 12375-81.
Jelesarov, I. and Karshikoff, A. (2009): Defining the role of salt bridges in protein stability. Methods in Molecular Biology, 490, 227-60
Pylaeva, S., Brehm, M., and Sebastiani D., (2018): Salt bridge in aqueous solution: strong structural motifs but weak enthalpic effect. Scientific Reports, (2018) 8: 13626.